tbuckley/cabot-search huggingface dataset:
Meiotic and mitotic aneuploidies drive arrest of in vitro fertilized human preimplantation embryos
Authors: Rajiv C. McCoy, Michael C. Summers, Abeo McCollin, Christian S. Ottolini, Kamal Ahuja, Alan H. Handyside
Journal: Genome Medicine (2023)

Abstract Background The high incidence of aneuploidy in early human development, arising either from errors in meiosis or postzygotic mitosis, is the primary cause of pregnancy loss, miscarriage, and stillbirth following natural conception as well as in vitro fertilization (IVF). Preimplantation genetic testing for aneuploidy (PGT-A) has confirmed the prevalence of meiotic and mitotic aneuploidies among blastocyst-stage IVF embryos that are candidates for transfer. However, only about half of normally fertilized embryos develop to the blastocyst stage in vitro, while the others arrest at cleavage to late morula or early blastocyst stages. Methods To achieve a more complete view of the impacts of aneuploidy, we applied low-coverage sequencing-based PGT-A to a large series ( n = 909) of arrested embryos and trophectoderm biopsies. We then correlated observed aneuploidies with abnormalities of the first two cleavage divisions using time-lapse imaging ( n = 843). Results The combined incidence of meiotic and mitotic aneuploidies was strongly associated with blastocyst morphological grading, with the proportion ranging from 20 to 90% for the highest to lowest grades, respectively. In contrast, the incidence of aneuploidy among arrested embryos was exceptionally high (94%), dominated by mitotic aneuploidies affecting multiple chromosomes. In turn, these mitotic aneuploidies were strongly associated with abnormal cleavage divisions, such that 51% of abnormally dividing embryos possessed mitotic aneuploidies compared to only 23% of normally dividing embryos. Conclusions We conclude that the combination of meiotic and mitotic aneuploidies drives arrest of human embryos in vitro, as development increasingly relies on embryonic gene expression at the blastocyst stage.
FTO fuels diabetes-induced vascular endothelial dysfunction associated with inflammation by erasing m6A methylation of TNIP1
Authors: Chuandi Zhou, Xinping She, Chufeng Gu, Yanan Hu, Mingming Ma, Qinghua Qiu, Tao Sun, Xun Xu, Haibing Chen, Zhi Zheng
Journal: Journal of Clinical Investigation (2023)

Endothelial dysfunction is a critical and initiating factor of the vascular complications of diabetes. Inflammation plays an important role in endothelial dysfunction regulated by epigenetic modifications. N6-methyladenosine (m6A) is one of the most prevalent epigenetic modifications in eukaryotic cells. In this research, we identified an m6A demethylase, fat mass and obesity-associated protein (FTO), as an essential epitranscriptomic regulator in diabetes-induced vascular endothelial dysfunction. We showed that enhanced FTO reduced the global level of m6A in hyperglycemia. FTO knockdown in endothelial cells (ECs) resulted in less inflammation and compromised ability of migration and tube formation. Compared with EC Ftofl/fl diabetic mice, EC-specific Fto-deficient (EC FtoΔ/Δ) diabetic mice displayed less retinal vascular leakage and acellular capillary formation. Furthermore, methylated RNA immunoprecipitation sequencing (MeRIP-Seq) combined with RNA-Seq indicated that Tnip1 served as a downstream target of FTO. Luciferase activity assays and RNA pull-down demonstrated that FTO repressed TNIP1 mRNA expression by erasing its m6A methylation. In addition, TNIP1 depletion activated NF-κB and other inflammatory factors, which aggravated retinal vascular leakage and acellular capillary formation, while sustained expression of Tnip1 by intravitreal injection of adeno-associated virus alleviated endothelial impairments. These findings suggest that the FTO-TNIP1-NF-κB network provides potential targets to treat diabetic vascular complications.
Reduction of SPARC protects mice against NLRP3 inflammasome activation and obesity
Authors: Seungjin Ryu, Olga Spadaro, Sviatoslav Sidorov, Aileen H. Lee, Sonia Caprio, Christopher Morrison, Steven R. Smith, Eric Ravussin, Irina Shchukina, Maxim N. Artyomov, Yun-Hee Youm, Vishwa Deep Dixit
Journal: Journal of Clinical Investigation (2023)

The comprehensive assessment of long-term effects of reducing intake of energy (CALERIE-II; NCT00427193) clinical trial established that caloric restriction (CR) in humans lowers inflammation. The identity and mechanism of endogenous CR-mimetics that can be deployed to control obesity-associated inflammation and diseases are not well understood. Our studies have found that 2 years of 14% sustained CR in humans inhibits the expression of the matricellular protein, secreted protein acidic and rich in cysteine (SPARC), in adipose tissue. In mice, adipose tissue remodeling caused by weight loss through CR and low-protein diet feeding decreased, while high-fat diet-induced (HFD-induced) obesity increased SPARC expression in adipose tissue. Inducible SPARC downregulation in adult mice mimicked CR's effects on lowering adiposity by regulating energy expenditure. Deletion of SPARC in adipocytes was sufficient to protect mice against HFD-induced adiposity, chronic inflammation, and metabolic dysfunction. Mechanistically, SPARC activates the NLRP3 inflammasome at the priming step and downregulation of SPARC lowers macrophage inflammation in adipose tissue, while excess SPARC activated macrophages via JNK signaling. Collectively, reduction of adipocyte-derived SPARC confers CR-like metabolic and antiinflammatory benefits in obesity by serving as an immunometabolic checkpoint of inflammation.
Mechanosensing Piezo channels in gastrointestinal disorders
Authors: Sandip M. Swain, Rodger A. Liddle
Journal: Journal of Clinical Investigation (2023)

All cells in the body are exposed to physical force in the form of tension, compression, gravity, shear stress, or pressure. Cells convert these mechanical cues into intracellular biochemical signals; this process is an inherent property of all cells and is essential for numerous cellular functions. A cell's ability to respond to force largely depends on the array of mechanical ion channels expressed on the cell surface. Altered mechanosensing impairs conscious senses, such as touch and hearing, and unconscious senses, like blood pressure regulation and gastrointestinal (GI) activity. The GI tract's ability to sense pressure changes and mechanical force is essential for regulating motility, but it also underlies pain originating in the GI tract. Recent identification of the mechanically activated ion channels Piezo1 and Piezo2 in the gut and the effects of abnormal ion channel regulation on cellular function indicate that these channels may play a pathogenic role in disease. Here, we discuss our current understanding of mechanically activated Piezo channels in the pathogenesis of pancreatic and GI diseases, including pancreatitis, diabetes mellitus, irritable bowel syndrome, GI tumors, and inflammatory bowel disease. We also describe how Piezo channels could be important targets for treating GI diseases.
Perilipin 2–positive mononuclear phagocytes accumulate in the diabetic retina and promote PPARγ-dependent vasodegeneration
Authors: Guillaume Blot, Rémi Karadayi, Lauriane Przegralek, Thérèse-Marie Sartoris, Hugo Charles-Messance, Sébastien Augustin, Pierre Negrier, Frédéric Blond, Frida Paulina Muñiz-Ruvalcaba, David Rivera-de la Parra, Lucile Vignaud, Aude Couturier, José-Alain Sahel, Niyazi Acar, Aida Jimenez-Corona, Cécile Delarasse, Yonathan Garfias, Florian Sennlaub, Xavier Guillonneau
Journal: Journal of Clinical Investigation (2023)

Type 2 diabetes mellitus (T2DM), characterized by hyperglycemia and dyslipidemia, leads to nonproliferative diabetic retinopathy (NPDR). NPDR is associated with blood-retina barrier disruption, plasma exudates, microvascular degeneration, elevated inflammatory cytokine levels, and monocyte (Mo) infiltration. Whether and how the diabetes-associated changes in plasma lipid and carbohydrate levels modify Mo differentiation remains unknown. Here, we show that mononuclear phagocytes (MPs) in areas of vascular leakage in DR donor retinas expressed perilipin 2 (PLIN2), a marker of intracellular lipid load. Strong upregulation of PLIN2 was also observed when healthy donor Mos were treated with plasma from patients with T2DM or with palmitate concentrations typical of those found in T2DM plasma, but not under high-glucose conditions. PLIN2 expression correlated with the expression of other key genes involved in lipid metabolism (ACADVL, PDK4) and the DR biomarkers ANGPTL4 and CXCL8. Mechanistically, we show that lipid-exposed MPs induced capillary degeneration in ex vivo explants that was inhibited by pharmaceutical inhibition of PPARγ signaling. Our study reveals a mechanism linking dyslipidemia-induced MP polarization to the increased inflammatory cytokine levels and microvascular degeneration that characterize NPDR. This study provides comprehensive insights into the glycemia-independent activation of Mos in T2DM and identifies MP PPARγ as a target for inhibition of lipid-activated MPs in DR.
The Mycobacterium tuberculosis genome at 25 years: lessons and lingering questions
Authors: Benjamin N Koleske, William R Jacobs, William R Bishai
Journal: Journal of Clinical Investigation (2023)

First achieved in 1998 by Cole et al., the complete genome sequence of Mycobacterium tuberculosis continues to provide an invaluable resource to understand tuberculosis (TB), the leading cause of global infectious disease mortality. At the 25-year anniversary of this accomplishment, we describe how insights gleaned from the M. tuberculosis genome have led to vital tools for TB research, epidemiology, and clinical practice. The increasing accessibility of whole-genome sequencing across research and clinical settings has improved our ability to predict antibacterial susceptibility, to track epidemics at the level of individual outbreaks and wider historical trends, to query the efficacy of the bacille Calmette-Guérin (BCG) vaccine, and to uncover targets for novel antitubercular therapeutics. Likewise, we discuss several recent efforts to extract further discoveries from this powerful resource.
Alveolar macrophages in tissue homeostasis, inflammation, and infection: evolving concepts of therapeutic targeting
Authors: Christina Malainou, Shifaa M Abdin, Nico Lachmann, Ulrich Matt, Susanne Herold
Journal: Journal of Clinical Investigation (2023)

Alveolar macrophages (AMs) are the sentinel cells of the alveolar space, maintaining homeostasis, fending off pathogens, and controlling lung inflammation. During acute lung injury, AMs orchestrate the initiation and resolution of inflammation in order to ultimately restore homeostasis. This central role in acute lung inflammation makes AMs attractive targets for therapeutic interventions. Single-cell RNA-Seq and spatial omics approaches, together with methodological advances such as the generation of human macrophages from pluripotent stem cells, have increased understanding of the ontogeny, function, and plasticity of AMs during infectious and sterile lung inflammation, which could move the field closer to clinical application. However, proresolution phenotypes might conflict with proinflammatory and antibacterial responses. Therefore, therapeutic targeting of AMs at vulnerable time points over the course of infectious lung injury might harbor the risk of serious side effects, such as loss of antibacterial host defense capacity. Thus, the identification of key signaling hubs that determine functional fate decisions in AMs is of the utmost importance to harness their therapeutic potential.
Logic-gated tumor-microenvironment nanoamplifier enables targeted delivery of CRISPR/Cas9 for multimodal cancer therapy
Authors: Yongchun Pan, Xiaowei Luan, Fei Zeng, Xuyuan Wang, Shurong Qin, Qianglan Lu, Guanzhong He, Yanfeng Gao, Xiaolian Sun, Xin Han, Bangshun He, Yujun Song
Journal: Acta Pharmaceutica Sinica B (2023)

Recent innovations in nanomaterials inspire abundant novel tumor-targeting CRISPR-based gene therapies. However, the therapeutic efficiency of traditional targeted nanotherapeutic strategies is limited by that the biomarkers vary in a spatiotemporal-dependent manner with tumor progression. Here, we propose a self-amplifying logic-gated gene editing strategy for gene/H
To Tip or Not to Tip: A New Combination for Precision Medicine in Head and Neck Cancer
Authors: Rex H. Lee, Daniel E. Johnson, Jennifer R. Grandis
Journal: Cancer Research (2023)

Abstract Meaningful advances in targeted therapy for head and neck squamous cell carcinoma (HNSCC) have been hampered by limited availability of robust preclinical models for translational research. Using an impressive array of in vitro and in vivo preclinical HNSCC models, Smith and colleagues demonstrated the efficacy of alpelisib and tipifarnib combination therapy through sustained mTOR inhibition in PIK3CA/HRAS-dysregulated HNSCC, including preliminary evidence of robust antitumor activity in a patient enrolled in a precision medicine trial. This study in this issue of Cancer Research illustrates the value of preclinical avatars for informing biomarker-driven clinical trials to advance precision medicine in HNSCC and other cancers. See related article by Smith et al., p. 3252
Reevaluating the Association Between Autism and Lithium Exposure During Pregnancy—Reply
Authors: Zeyan Liew, Ole Raaschou-Nielsen, Beate Ritz
Journal: JAMA Pediatrics (2023)

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Ideography, Blissymbolics, standardization, and emergent conformity
Authors: Harry Howard
Journal: Behavioral and Brain Sciences (2023)

Abstract There is an extensive literature on the usage of Blissymbolics in augmentative and alternative communication that contradicts Morin's contention that it fails as an ideography. Morin's notion of “standardization” (target article, sect. X, para. X) is at odds with the highly developed understanding of this notion in linguistics. What Morin seems to have in mind corresponds to the notion of emergence in iterative and multiagent models of language learning.
Survival Trend in Individuals With De Novo Metastatic Prostate Cancer After the Introduction of Doublet Therapy
Authors: Christian Corsini, Hans Garmo, Andri Wilberg Orrason, Rolf Gedeborg, Pär Stattin, Marcus Westerberg
Journal: JAMA Network Open (2023)

Recently, life-prolonging treatments for patients with advanced prostate cancer have been introduced in clinical practice.To investigate if the introduction of doublet therapy is associated with changes in survival on a population-basis.This nationwide population-based cohort study used data from the Prostate Cancer data Base Sweden from 2008 to 2020. Men registered with de novo metastatic castration-sensitive prostate cancer (mCSPC) were included.The proportion of men with mCSPC who received doublet therapy, ie, androgen deprivation therapy plus androgen receptor pathway inhibitor drugs or chemotherapy was assessed.Standardized overall survival, taking age, comorbidity, and cancer characteristics into consideration, was estimated by use of a parametric survival model.A total of 11 382 men were included in this study (median [IQR] age, 74.0 [68-81] years). There was a shift toward less advanced prostate cancer during the study period with a decrease in median (IQR) prostate-specific antigen at diagnosis in men with mCSPC from 145 (39-571) ng/mL to 107 (27-426) ng/mL. Upfront treatment with doublet therapy in these men simultaneously increased from 1% (7 of 991) in 2016 to 44% (402 of 922) in 2020. The adjusted 5-year overall survival increased from 26% (95% CI, 25%-28%) from 2008 to 2012 to 35% (95% CI, 31%-40%) from 2017 to 2020. During the first 5 years after diagnosis, there was an increase in mean survival of 6 months, from 2.7 (95% CI, 2.6-2.8) years from 2008 to 2012 to 3.2 (95% CI, 3.1-3.1) years from 2017 to 2020.In parallel with improvements in treatment of advanced prostate cancer, a clinically meaningful increase in mean survival was observed in men with de novo mCSPC in Sweden between 2008 and 2020 in this study.
A source- and channel-coding approach to the analysis and design of languages and ideographies
Authors: Mihnea Moldoveanu
Journal: Behavioral and Brain Sciences (2023)

Abstract Can we explain the advantage natural languages enjoy over ideographies in a way that enables us to attempt the design of an ideography that “works”? I deploy an adapted version of Shannon's source- and channel-coding partitioning of a communication system to explain the communicative dynamics and shortfalls of ideographies, and reveal ways in which entrenchable, generalist ideographies could be designed.
Silky Liquid Metal Electrodes for On‐Skin Health Monitoring
Authors: Maria A. Menke, Braden M. Li, Meghan G. Arnold, Logan E. Mueller, Robin Dietrich, Shijie Zhou, Nancy Kelley‐Loughnane, Patrick Dennis, Jason T. Boock, Joseph Estevez, Christopher E. Tabor, Jessica L. Sparks
Journal: Advanced Healthcare Materials (2023)

Abstract Next generation on‐skin electrodes will require soft, flexible, and gentle materials to provide both high‐fidelity sensing and wearer comfort. However, many commercially available on‐skin electrodes lack these key properties due to their use of rigid hardware, harsh adhesives, uncomfortable support structures, and poor breathability. To address these challenges, this work presents a new device paradigm by joining biocompatible electrospun spider silk with printable liquid metal to yield an incredibly soft and scalable on‐skin electrode that is strain‐tolerant, conformable, and gentle on‐skin. These electrodes, termed silky liquid metal (SLiM) electrodes, are found to be over five times more breathable than commercial wet electrodes, while the silk's intrinsic adhesion mechanism allows SLiM electrodes to avoid the use of harsh artificial adhesives, potentially decreasing skin irritation and inflammation over long‐term use. Finally, the SLiM electrodes provide comparable impedances to traditional wet and other liquid metal electrodes, offering a high‐fidelity sensing alternative with increased wearer comfort. Human subject testing confirmed the SLiM electrodes ability to sense electrophysiological signals with high fidelity and minimal irritation to the skin. The unique properties of the reported SLiM electrodes offer a comfortable electrophysiological sensing solution especially for patients with pre‐existing skin conditions or surface wounds.
Small EV-based delivery of CpG ODNs for melanoma postsurgical immunotherapy
Authors: Yutong Lu, Hao Ye, Jian Zhao, Kaiyuan Wang, Xiaoyuan Fan, Qi Lu, Liping Cao, Bin Wan, Fengxiang Liu, Fei Sun, Xiaofeng Chen, Zhonggui He, Hongzhuo Liu, Jin Sun
Journal: Journal of Controlled Release (2023)
Levetiracetam vs Lamotrigine as First-Line Antiseizure Medication in Female Patients With Idiopathic Generalized Epilepsy
Authors: Emanuele Cerulli Irelli, Enrico Cocchi, Alessandra Morano, Joanna Gesche, Roberto H. Caraballo, Simona Lattanzi, Gionata Strigaro, Cecilia Catania, Edoardo Ferlazzo, Angelo Pascarella, Sara Casciato, Pierpaolo Quarato, Chiara Pizzanelli, Patrizia Pulitano, Loretta Giuliano, Veronica Viola, Barbara Mostacci, Francesco Fortunato, Carla Marini, Giancarlo Di Gennaro, Antonio Gambardella, Angelo Labate, Francesca F. Operto, Anna T. Giallonardo, Betul Baykan, Christoph P. Beier, Carlo Di Bonaventura, Daniela Fatuzzo, Eleonora Rosati, Giulio Pastorelli, Biagio Sancetta, Giovanni Assenza, Mario Tombini, Emanuela Viglietta, Pietro Pignatta, Vittoria Cianci, Irene Bagnasco, Edoardo Pronello, Marta Piccioli, Chiara Milano, Domenica Battaglia, Marco Perulli, Francesca Bisulli, Martina Fanella, Roberto De Simone, Giuseppe Pontrelli, Giovanni Boero, Francesca Gilio, Francesca Gragnani, Biagio Orlando, Adolfo Mazzeo, Chiara Panzini
Journal: JAMA Neurology (2023)

After the recent limitations to prescribing valproate, many studies have highlighted the challenging management of female patients of reproductive age with idiopathic generalized epilepsy (IGE). However, no study, to the authors' knowledge, has addressed the comparative effectiveness of alternative antiseizure medications (ASMs) in these patients.
Dependence of sonoporation efficiency on microbubble size: An in vitro monodisperse microbubble study
Authors: Benjamin van Elburg, Joke Deprez, Martin van den Broek, Stefaan C. De Smedt, Michel Versluis, Guillaume Lajoinie, Ine Lentacker, Tim Segers
Journal: Journal of Controlled Release (2023)

Sonoporation is the process where intracellular drug delivery is facilitated by ultrasound-driven microbubble oscillations. Several mechanisms have been proposed to relate microbubble dynamics to sonoporation including shear and normal stress. The present work aims to gain insight into the role of microbubble size on sonoporation and thereby into the relevant mechanism(s) of sonoporation. To this end, we measured the sonoporation efficiency while varying microbubble size using monodisperse microbubble suspensions. Sonoporation experiments were performed in vitro on cell monolayers using a single ultrasound pulse with a fixed frequency of 1 MHz while the acoustic pressure amplitude and pulse length were varied at 250, 500, and 750 kPa, and 10, 100, and 1000 cycles, respectively. Sonoporation efficiency was quantified using flow cytometry by measuring the FITC-dextran (4 kDa and 2 MDa) fluorescence intensity in 10,000 cells per experiment to average out inherent variations in the bioresponse. Using ultra-high-speed imaging at 10 million frames per second, we demonstrate that the bubble oscillation amplitude is nearly independent of the equilibrium bubble radius at acoustic pressure amplitudes that induce sonoporation (≥ 500 kPa). However, we show that sonoporation efficiency is strongly dependent on the equilibrium bubble size and that under all explored driving conditions most efficiently induced by bubbles with a radius of 4.7 μm. Polydisperse microbubbles with a typical ultrasound contrast agent size distribution perform almost an order of magnitude lower in terms of sonoporation efficiency than the 4.7-μm bubbles. We elucidate that for our system shear stress is highly unlikely the mechanism of action. By contrast, we show that sonoporation efficiency correlates well with an estimate of the bubble-induced normal stress.